Embryo implantation is a critical step in mammalian reproduction. At this point the embryo forms a more intimate connection with the maternal uterine tissues. In many mammals this involves physical attachment of the embryo to the uterus with subsequent invasion of the maternal tissues by the embryonic trophoblast. The uterus responds to the invading embryo by decidualizing which acts to both restrict embryo invasion and to nurture the implanted embryo. In anticipation of implantation the uterus undergoes a series of proliferative and differentiative changes under control of the ovarian steroid hormones, estrogen and progesterone that act either directly on cells or via the induction of locally produced growth factors and cytokines. Among the latter is Leukemia Inhibitory Factor (LIF) that we first showed inhibited the differentiation of mouse embryonic stem (ES) cells. In mice and other mammals, including humans, LIF is strongly expressed in the uterus at the time of implantation and that in mice this is under the control of estrogen. LIF is essential for embryo implantation, as female mice lacking a functional LIF gene are sterile with the blastocysts failing to implant. We are currently investigating how LIF affects uterine receptivity, what signal transduction pathways are activated and how these are regulated by the steroid hormones. We are also interested in identifying genes that are controlled by LIF in the uterus and are developing tissues specific means by which we can manipulate their expression to determine their function. These studies should help understand some of the major causes of infertility. They may also provide insights as to how epithelial-stromal interactions are mediated by steroid hormones and growth factors. The latter should help understand how and why many cancers arise from epithelial cell populations in the body.